Inosine-5-monophosphate dehydrogenase (IMPDH) catalyzes the conversion of IMP to XMP, the first and rate-limiting step of guanine nucleotide biosynthesis. The isozymes IMPDH1 and IMPDH2 are encoded by two distinct genes. Research studies show that IMPDH2 is overexpressed in glioblastoma. In glioblastoma, IMPDH2-mediated GTP biosynthesis is essential for rRNA and tRNA synthesis and the formation of enlarged and irregular nucleoli. In addition, IMPDH1 and IMPDH2 double knockout leads to significant inhibition of tumor growth in an orthotopic glioblastoma model. Furthermore, IMPDH1 and IMPDH2 expression is upregulated in small cell lung cancer cells with low expression of ASCL1 transcription factor (ASCL1Low). Suppression of IMPDH activity inhibits ASCL1Low small cell lung cancer growth.
